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Open Access Review Unravelling signal escape ... FAILURE TO FIRST-LINE TREATMENT IN PATIENTS WITH ADVANCED EGFR-MUTANT NSCLC EGFR mutations predict sensitivity to the first-generation

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  • Unravelling signal escape through maintained EGFR activation in advanced non-small cell lung cancer (NSCLC): new treatment options

    Jordi Remon,1 Benjamin Besse1,2

    To cite: Remon J, Besse B. Unravelling signal escape through maintained EGFR activation in advanced non- small cell lung cancer (NSCLC): new treatment options. ESMO Open 2016;1: e000081. doi:10.1136/ esmoopen-2016-000081

    ▸ Prepublication history and additional material for this paper is available online. To view these files please visit the journal online (http://dx.doi.org/10.1136/ esmoopen-2016-000081).

    Received 2 June 2016 Accepted 30 June 2016

    1Medical Oncology Department, Gustave Roussy, Université Paris-Saclay, Villejuif, France 2Paris Sud University, Orsay, France

    Correspondence to Dr Benjamin Besse; [email protected] gustaveroussy.fr

    ABSTRACT The discovery of activating epidermal growth factor receptor (EGFR) mutations has opened up a new era in the development of more effective treatments for patients with non-small cell lung cancer (NSCLC). However, patients with EGFR-activating mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) ultimately develop acquired resistance (AR). Among known cases of patients with AR, 70% of the mechanisms involved in the development of AR to EGFR TKI have been identified and may be categorised as either secondary EGFR mutations such as the T790M mutation, activation of bypass track signalling pathways such as MET amplification, or histologic transformation. EGFR-mutant NSCLC tumours maintain oncogenic addiction to the EGFR pathway beyond progression with EGFR TKI. Clinical strategies that can be implemented in daily clinical practice to potentially overcome this resistance and prolong the outcome in this subgroup of patients are presented.

    INTRODUCTION Lung cancer is the third most frequent cancer (1.82 million cases) and the leading cause of cancer-related death (1.59 million deaths) worldwide according to the GLOBOCAN 2012 database.1 The current SEER database shows that 16% of non-small cell lung cancers (NSCLCs) are diagnosed at localised stage (for which surgery remains the standard treatment for fit patients), 22% of patients are diagnosed with locally advanced disease and up to 60% with advanced stage.2 Historically, platinum-based doublet chemotherapy has been the stand- ard first-line treatment for non-selected patients with advanced NSCLC who have a good performance status.3 The knowledge of genomic alterations in lung cancer has impli- cations for the management of this disease.4

    The introduction of targeted therapies, based on the recognition of the significance of acquired genetic driver mutations, has

    changed the treatment paradigm of patients with lung cancer, establishing tumour geno- typing as an essential routine diagnostic tool in clinical practice, notably in cases of adeno- carcinoma histology.5 Different types of mutations have been reported in lung adeno- carcinomas,4 but only 20–25% of them are actionable oncogenic driver mutations.6 It has been reported that patients with NSCLC with a tumour harbouring known oncogenic drivers and who receive a matched targeted agent live significantly longer than those who have a driver mutation but do not receive personalised treatment (HR, 0.69; 95% CI 0.53 to 0.90; p=0.006),7 supporting the clin- ical benefit of this policy.6

    In Caucasian patients, the most frequent genetic alterations in advanced adenocarcin- oma lung cancer are the KRAS mutation ∼29%, epidermal growth factor receptor (EGFR) mutations ∼11%, ALK rearrange- ments ∼5%6 and MET mutations (exon 14) in 4%.8 Other less frequent mutations include BRAF and PIK3CA mutations in ∼2% each, the HER2 mutation in 1% of tumours6

    and ROS1 rearrangements9 in 1% of patients with NSCLC. These oncogenic drivers are almost always mutually exclusive in this patient population.7

    There are several classes of activating somatic EGFR mutations, with in-frame dele- tions in exon 19 (ELREA, Del19) and single- point mutations in exon 21 (L858R) being the most frequent. These mutations are markedly more frequent in the Asian than in the Caucasian population (∼50% vs 10%).10

    In this review, we summarise the state of play for current treatments in the EGFR-mutant population for different treatment settings following acquired resistance (AR) and present the rationale behind new approaches being investigated following development resistance.

    Remon J, et al. ESMO Open 2016;1:e000081. doi:10.1136/esmoopen-2016-000081 1

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  • FAILURE TO FIRST-LINE TREATMENT IN PATIENTS WITH ADVANCED EGFR-MUTANT NSCLC EGFR mutations predict sensitivity to the first-generation reversible EGFR tyrosine kinase inhibitors (TKIs) erloti- nib and gefitinib and to the second-generation irrevers- ible EGFR TKIs such as afatinib and dacomitinib. All four of these drugs have demonstrated improvement in the response rate (RR), progression-free survival (PFS) and quality of life over standard first-line platinum- doublet chemotherapy in at least nine randomised phase III trials in patients with advanced EGFR-mutant NSCLC. To date, no differences in overall survival (OS) versus standard platinum-doublet chemotherapy have been reported in these trials, possibly due to the high crossover rate to the TKI arm following disease progres- sion in chemotherapy-treated patients.11 A pooled ana- lysis of two randomised phase III trials (LUX-Lung 3 and LUX-Lung 6), which compared afatinib versus first- line chemotherapy, reported that although afatinib did not improve OS in the whole population of either trial, OS was improved with the drug for patients with Del19 EGFR mutations.12 In a recent meta-analysis of seven trials (1649 patients) evaluating EGFR TKIs, the EGFR TKI benefit over standard first-line chemotherapy was 50% greater for tumours with the Del19 mutation (HR, 0.24; 95% CI 0.20 to 0.29) than for those with the exon 21 L858R substitution (HR, 0.48; 95% CI 0.39 to 0.58; p

  • still unknown.24 There is no well-defined strategy for EGFR TKI AR, and the patients are managed according to known mechanisms of AR or disease progression patterns.25

    PERSISTING ONCOGENIC ADDICTION TO THE EGFR PATHWAY BEYOND PROGRESSION Persistent inhibition of tumour-dependent pathways beyond progression is a therapeutic strategy, which can be exploited in cancers in which there is a reliance on a single pathway for growth and proliferation. This ‘addic- tion’ is seen in various cancers such as advanced pros- tate cancer, which remains almost uniformly dependent on androgen receptor despite acquired resistant to hor- monal therapies such as castration,26 or HER2-positive advanced breast cancers, which can achieve an outcome at different HER2 inhibitors.27 Similarly, EGFR-mutant NSCLC maintains dependence on EGFR signalling even after the development of AR,28 29 and many trials have studied the impact of intensifying EGFR inhibition con- tinuing the same EGFR TKI beyond progression, or using a second-generation irreversible EGFR TKI as a monotherapy or in combination with anti-EGFR mono- clonal antibodies.

    Continuing single-agent EGFR TKIs beyond progression Some patients with EGFR-mutant NSCLC have indolent progression, and the patients may be treated with an EGFR TKI beyond RECIST progression if there is no clinical evidence of deterioration or intolerable tox- icity.30 In the retrospective SLADB study,31 the median

    PFS according to the physician criteria was 14.0, whereas in the prospective EURTAC trial,32 the same group had a median PFS of 9.7 months according to the RECIST criteria. Continuing EGFR TKI beyond RECIST progres- sion may delay salvage systemic therapy for a year or more.33 Recently, the phase II ASPIRATION trial con- ducted in 208 Asian patients with NSCLC, whose tumour harbours common EGFR mutations, and treated with first-line erlotinib reported that continuing erloti- nib beyond RECIST progression improved PFS by 3.9 months (from 11.0 to 14.9 months).34 However, the lack of an optimal control arm, the fact that the decision to continue erlotinib at progression was at the investiga- tors’ or patients’ discretion and the unknown local ther- apies administered diminish strength of the study. Taken together, the results of these studies suggest that con- tinuing EGFR TKI beyond RECIST progression is an adequate strategy for patients with good performance status, progression in previously identified lesions,35 a longer time to progression on EGFR TKI33 and no more than one metastatic site.36

    Switching to second-generation irreversible EGFR TKIs Second-generation irreversible EGFR TKIs such as afati- nib12 and dacomitinib37 are effective in the treatment of untreated EGFR-mutant lung cancers, although, as a monotherapy, they failed to overcome T790M-mediated resistance.38 Two phase II trials have tested the efficacy of afatinib in patients with advanced NSCLC who pro- gressed after one or two lines of chemotherapy and with at least 12 weeks of erlotinib and/or gefitinib. In the

    Figure 1 Main mechanisms of AR to EGFR TKI in EGFR-mutant NSCLC cells. AR, acquired resistance; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; M, mutated; NSCLC, non-sm

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